The present invention relates to metallo-organic cobalt compounds and their use in the prophylactic treatment of subjects to prevent chlamydia infections.
It has been discovered that certain conditions and diseases, e.g., inflammation, burns, wounds, and diseases caused by bacteria, fungi and viruses in mammalian species can be treated with certain complexes of cobalt having the structure: 
wherein
each A may be the same or different and is an alkyl group, a phenyl group or a substituted derivative of a phenyl group;
wherein each Y may be the same or different and is hydrogen, an unbranched alkyl group, a halide or a group having the structure 
wherein R is hydrogen, an alkoxide group, and alkyl group, or OH;
wherein each B may be the same or different and each is hydrogen or an alkyl group;
wherein each X may be the same or different and each is a water soluble group having weak to intermediate ligand filed strength; and
Zxe2x88x92 is a soluble, pharmaceutically acceptable negative ion.
Today, chlamydia infections are known to be significant causes of morbidity in human and veterinary medicine. Many of these infections present no noticable symptoms, yet can lead to sterility. New prophylactic treatments would decrease the incidence of these infections and improve overall health.
We have discovered a prophylactic use for the series of compounds having the structure: 
wherein
each A may be the same or different and is an alkyl group, a phenyl group or a substituted derivative of a phenyl group;
each Y may be the same or different and is hydrogen, an unbranched alkyl group, a halide or a group having the structure 
wherein R is hydrogen, an alkoxide group, an alkyl group, or OH;
each B may be the same or different and each is hydrogen or an alkyl group;
Zxe2x88x92 is a soluble, pharmaceutically acceptable negative ion; and
each X may be the same or different and is an axial ligand selected from the group consisting of moieties having the formula: 
wherein R1, R2, R3, and R4 may be the same or different and maybe hydrogen or lower alkyl having from 1 to 4 carbon atoms; and 
wherein R5, R6, R7, R8 and R9 may be the same or different and may be selected from the group consisting of electron donating groups and electron withdrawing groups;
with the proviso that R1, R2, R3, R4, R5, R6, R7, R8 and R9 are of a sufficiently small size so as not to prohibit the attachment of the axial ligand to the Co atom due to steric hindrance.
As used herein, the term xe2x80x9caxialxe2x80x9d when used in conjunction with the term xe2x80x9cligandxe2x80x9d refers to the fact that the ligand is oriented outside the plane of the molecule and has the same meaning as described in connection with FIG. 1 of U.S. Pat. No. 5,049,557. As used herein, and unless otherwise indicated, an alkyl group means a linear, branched or cyclic alkyl group containing from one to six carbon atoms.
The compounds having the structure of Formula II exhibit prophylactic efficacy when applied as a topical composition to the contact site prior to contact with chlamydia and/or by inactivating chlamydia exposed to the composition. The compositions of the invention may further be used for antisepsis or disinfection of surfaces, such as, surgical tools or preparations such as, media or blood-derived products, which are contaminated with chlamydia.
The compounds used in the present invention may be crystallized with numerous counter-anions. Counter-anions which are pharmaceutically acceptable and are water soluble, such as, halide ions, PF6xe2x88x92 and BF4xe2x88x92, are preferred. The bromide and chloride salts of the present compounds are the most preferred because they are more water soluble than other salts of the compounds.
As discussed above, A may be an alkyl group, a phenyl group or a substituted derivative of a phenyl group. Preferably, the alkyl group is a C1-C5 group with methyl, ethyl, and butyl groups being particularly preferred. Suitable substituted derivatives of the phenyl group are derivatives wherein each substituent is a halide, an alkyl group or a group having the structure 
wherein R is hydrogen, an alkoxide group, an alkyl group or an OH group. To date, the most useful derivatives have proven to be those in which the substituents are halides, or alkyl groups.
Y may be hydrogen, an unbranched alkyl group, a halide or a group having the structure 
wherein R is hydrogen, an alkoxide group, an alkyl group or an OH group. In certain embodiments, it is preferred that Y is chlorine, a hydrogen atom or a C1-C3 alkyl group. In embodiments where Y has a structure 
is preferred that R is hydrogen, a methyl group or an OH group.
B may be hydrogen or an alkyl group, and preferably is a C1-C3 alkyl group.
X may be imidazole or pyridinyl groups linked to the cobalt atom through a nitrogen of the ring. The imidazole or pyridinyl nuclei may have hydrogen atoms, or electron donating or withdrawing groups substituted thereon.
The electron withdrawing or donating groups which may constitute appendant groups R1, R2, R3, R4, R5, R6, R7 and R8 are those known in the art to exert the specified electron withdrawing or donating effects on aromatic nuclei. Typical of electron donating groups are NO2xe2x88x92, Clxe2x88x92, Brxe2x88x92, and the like. The identity of the particular group is not crucial so long as it does not impart properties to the molecules which are detrimental to the desired properties of the compound, e.g., decreased antiviral activity, increased toxicity, and the like. Additionally, the group must not be so large as to prevent the axial ligand to attach to the cobalt atom due to steric effects, e.g., steric hindrance.
Preferably, the groups attached to the imidazole nucleus are alkyl having from one to three carbon atoms. Of these, methyl and ethyl are most preferred. Preferred are the unsubstituted, 2-methyl, 4-methyl, and 2-ethyl imidazoles and the unsubstituted pyridinyl.
The following Table provides the structures of preferred compounds in accordance with the present invention. Compound 23, which is disclosed in U.S. Pat. No. 5,142,076 as exhibiting antiviral activity, is included as a comparison in the examples that follow.
In the following diagram, B is, in each case, methyl, and A, Y, X and Zxe2x88x92 refer to those symbols as used in structure II.
xe2x80x9cChlamydiaxe2x80x9d is used herein to mean any one or more of the bacteria in the genus chlamydia. The genus chlamydia includes the species C. pneumoniae, C. psittaci and C. trachomatis. 
The compositions used in the instant invention include a pharmaceutically acceptable carrier and a compound as defined above in a chlamydia prophylactic effective amount. As used herein, the expressions chlamydia prophylactic effective amount, dosage or regimen mean that amount, dosage or regimen which results in a sufficient concentration of the particular compound at an appropriate site to reduce the risk of infection by chlamydia. By appropriate site, it is meant a site which potentially contains chlamydia or is an area of a subject of potential exposure to chlamydia or is an area of a subject that has been exposed to chlamydia but as a result of such exposure, the subject has not yet acquired chlamydia disease. As used herein, the expression acquired chlamydia disease means that the subject, in fact, has the disease and can no longer be treated prophylactically to reduce the risk of infection by chlamydia, but, rather, must be treated therapeutically to cure, ameliorate or reduce the effects of the disease.
For topical administration, the inventive composition may be placed in a pharmaceutically acceptable aqueous solution, ointment, salve, cream or the like. The compounds used in the present invention are water soluble, although the degree of solubility may vary from compound to compound, and may be dissolved in a number of conventional pharmaceutically acceptable carriers. Suitable carriers include polar, protic solvents, such as, water, or normal saline, or non-polar solvents, lipids and the like. The compounds may also be suspended in a suspension medium that is not miscible with water, for example, petrolatum, or may be formulated in an emulsion (water-in-oil or oil-in-water).
When the compounds of formula II are to be administered by the topical route for prevention of infection, i.e., prophylaxis or disinfection, their concentration in an aqueous solution, ointment, salve, creme, or the like can vary from about 0.00005% to about 5% by weight. A preferred concentration range lies between about 0.0005% and about 2% by weight. A particularly preferred concentration range is from about 0.5% to about 2%. Typically, the topical composition shows prophylactic effect when applied to the contact site from about 1 hour before contact with chlamydia to about 6 hours after contact with chlamydia. Preferably, the topical composition is applied within five minutes of contact with chlamydia. More particularly, the inventive compositions can be applied intravaginally for the prevention of sexually transmitted diseases. The topical composition containing the inventive compound could, for example, be applied with an applicator or an intravaginal device or the topical composition could be coated on a condom or other sexual barrier devices.
When the compounds of formula II are to be used for disinfecting liquid preparations, such as, media, blood-derived products or the like, their concentration in the liquid preparations is from about 0.005% to about 5% by weight. A preferred concentration range lies between about 0.05% and about 5% by weight. A most preferred concentration range lies between about 0.01% and about 2% by weight.
General methods for the synthesis of the compounds of the present invention are described in U.S. Pat. No. 5,049,557, referred to and incorporated by reference hereinabove. As noted therein, the reaction of Co(II) complexes with molar oxygen has been studied extensively (see, R. S. Drago and B. R. Corden, Acc. Chem. Res., 1980, 13, 353 and E. C. Niederhoffer, J. H. Timmons and A. E. Martell, Chem. Rev. 1984, 84, 137). Normally, cobalt (II) forms 2:1 peroxo bridged complexes in aqueous solutions (see E. C. Niederhoffer, J. H. Timmons and A. E. Martell, Chem. Rev. 1984, 84, 137). In recent years, a number of Co(II) complexes have been reported to give 1:1 cobalt-oxygen adducts at room temperature. These complexes usually contain ligands which when bound to Co(II) give rise to a low spin planar geometry. Addition of base and O2 to these complexes leads to the formation of octahedral complexes where the base and the O2 occupy axial positions (see, A. Summerville, R. D. Jones, B. M. Hoffman and F. Basolo, J.Chem. Educ., 1979, 56, 3, 157).
On the basis of measurements utilizing a variety of physical techniques, it is now a well-accepted fact that the most accurate electronic structure description of the Co:O2 moiety is a Co(III) ion bound to O2xe2x88x92 where the actual amount of Coxe2x86x92O2 electron transfer depends on the nature of the ligand and the donor set (see, A. Summerville, R. D. Jones, B. M. Hoffman and F. Basolo, J. Chem. Educ. 1979, 56, 3 157, and D. Getz, E. Malmud, B. L. Silver and Z. Dori, J. Am Chem. Soc., 1975, 97, 3846). It has been shown that electron transfer increases with increase of the ligand field strength (see, R. S. Drago and B. R. Corden, Acc. Chem. Res., 1980, 13, 353). This can be easily understood from the molecular orbital diagram depicted in FIG. 1 of U.S. Pat. No. 5,049,557 and the description therein.